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1.
Pan Afr Med J ; 38: 350, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367429

RESUMO

Introduction: sickle cell disease is one of the greatest public health problems of this age. This study was conducted to assess the knowledge, attitude and control practices on sickle cell disease (SCD) among selected secondary school students in Osun State, Nigeria. Methods: a descriptive cross-sectional study involved 420 secondary school students within Osogbo Metropolis selected by a multistage stratified sampling technique, using self-administered structured questionnaire. Data were collected using pre-tested self-administered semi structured questionnaire. Data were analyzed using SPSS version 20. Results: a total of 420 students were interviewed, modal age range 15-20 years. There were more females (55%) than males (45%). Majority of them were christians (57.1%). A larger percentage of the respondents were aware of SCD (58.5%). However, comprehensive knowledge as regards the various genotypes related to SCD, tests to be done for genotype screening among the respondents is low. One third of the respondents had positive attitude towards SCD (65%) and nearly one half (48%) of the respondents had bad control practices. Conclusion: findings in this study shows a high level of general awareness on SCD, even though comprehensive knowledge as regards the various genotype related to SCD, tests to be done for genotype screening among others is low. The need to improve on their attitude and practice towards the disease is highly recommended because having a good knowledge is not as important as applying the knowledge in a way to stop the spread of the disease.


Assuntos
Anemia Falciforme/prevenção & controle , Testes Genéticos/métodos , Conhecimentos, Atitudes e Prática em Saúde , Estudantes/estatística & dados numéricos , Adolescente , Anemia Falciforme/genética , Criança , Estudos Transversais , Feminino , Genótipo , Humanos , Masculino , Nigéria , Inquéritos e Questionários , Adulto Jovem
2.
Int J Mol Sci ; 22(16)2021 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-34445333

RESUMO

Lynch syndrome (LS) is one of the most common hereditary cancer predisposition syndromes worldwide. Individuals with LS have a high risk of developing colorectal or endometrial cancer, as well as several other cancers. LS is caused by autosomal dominant pathogenic variants in one of the DNA mismatch repair (MMR) genes MLH1, MSH2, PMS2 or MSH6, and typically include truncating variants, such as frameshift, nonsense or splicing variants. However, a significant number of missense, intronic, or silent variants, or small in-frame insertions/deletions, are detected during genetic screening of the MMR genes. The clinical effects of these variants are often more difficult to predict, and a large fraction of these variants are classified as variants of uncertain significance (VUS). It is pivotal for the clinical management of LS patients to have a clear genetic diagnosis, since patients benefit widely from screening, preventive and personal therapeutic measures. Moreover, in families where a pathogenic variant is identified, testing can be offered to family members, where non-carriers can be spared frequent surveillance, while carriers can be included in cancer surveillance programs. It is therefore important to reclassify VUSs, and, in this regard, functional assays can provide insight into the effect of a variant on the protein or mRNA level. Here, we briefly describe the disorders that are related to MMR deficiency, as well as the structure and function of MSH6. Moreover, we review the functional assays that are used to examine VUS identified in MSH6 and discuss the results obtained in relation to the ACMG/AMP PS3/BS3 criterion. We also provide a compiled list of the MSH6 variants examined by these assays. Finally, we provide a future perspective on high-throughput functional analyses with specific emphasis on the MMR genes.


Assuntos
Proteínas de Ligação a DNA/genética , Técnicas Genéticas , Animais , Proteínas de Ligação a DNA/classificação , Proteínas de Ligação a DNA/fisiologia , Testes Genéticos/métodos , Humanos , Proteínas Mutantes/classificação , Proteínas Mutantes/genética , Proteínas Mutantes/fisiologia , Isoformas de Proteínas/classificação , Isoformas de Proteínas/genética , Isoformas de Proteínas/fisiologia , Splicing de RNA/genética
4.
Genes (Basel) ; 12(6)2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34204358

RESUMO

Pediatric acute myeloid leukemia is a rare and heterogeneous disease in relation to morphology, immunophenotyping, germline and somatic cytogenetic and genetic abnormalities. Over recent decades, outcomes have greatly improved, although survival rates remain around 70% and the relapse rate is high, at around 30%. Cytogenetics is an important factor for diagnosis and indication of prognosis. The main cytogenetic abnormalities are referenced in the current WHO classification of acute myeloid leukemia, where there is an indication for risk-adapted therapy. The aim of this article is to provide an updated review of cytogenetics in pediatric AML, describing well-known WHO entities, as well as new subgroups and germline mutations with therapeutic implications. We describe the main chromosomal abnormalities, their frequency according to age and AML subtypes, and their prognostic relevance within current therapeutic protocols. We focus on de novo AML and on cytogenetic diagnosis, including the practical difficulties encountered, based on the most recent hematological and cytogenetic recommendations.


Assuntos
Aberrações Cromossômicas , Leucemia Mieloide Aguda/genética , Adolescente , Criança , Pré-Escolar , Testes Genéticos/métodos , Humanos , Hibridização in Situ Fluorescente/métodos , Lactente , Cariotipagem/métodos , Leucemia Mieloide Aguda/patologia
5.
Urol Clin North Am ; 48(3): 297-309, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34210486

RESUMO

Germline genetic testing for prostate cancer (PC) is increasingly important as the clinical utility of germline variants in this patient population is understood better. To better characterize the clinical landscape of germline testing in PC, published clinical cohorts of PC who underwent clinical germline genetic analysis at point of care are reviewed. Limitations and heterogeneity of these cohorts are highlighted and pathogenic results with established or potential clinical utility in PC noted. The need for additional germline genetic studies is underscored, because the number of PC patients studied lags greatly behind the high prevalence of the disease.


Assuntos
Predisposição Genética para Doença , Testes Genéticos/métodos , Neoplasias da Próstata/genética , Progressão da Doença , Aconselhamento Genético , Mutação em Linhagem Germinativa , Humanos , Masculino , Neoplasias da Próstata/etnologia
6.
Int J Mol Sci ; 22(13)2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-34281208

RESUMO

Next-generation sequencing (NGS) is the technology of choice for the routine screening of tumor samples in clinical practice. In this setting, the targeted sequencing of a restricted number of clinically relevant genes represents the most practical option when looking for genetic variants associated with cancer, as well as for the choice of targeted treatments. In this review, we analyze available NGS platforms and clinical applications of multi-gene testing in breast cancer, with a focus on metastatic triple-negative breast cancer (mTNBC). We make an overview of the clinical utility of multi-gene testing in mTNBC, and then, as immunotherapy is emerging as a possible targeted therapy for mTNBC, we also briefly report on the results of the latest clinical trials involving immune checkpoint inhibitors (ICIs) and TNBC, where NGS could play a role for the potential predictive utility of homologous recombination repair deficiency (HRD) and tumor mutational burden (TMB).


Assuntos
Testes Genéticos/métodos , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Biomarcadores Tumorais/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Humanos , Mutação/genética , Neoplasias de Mama Triplo Negativas/patologia
7.
Int J Mol Sci ; 22(13)2021 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-34281261

RESUMO

Inherited retinal diseases (IRDs) are a heterogeneous group of conditions that include retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EO[S]RD), which differ in severity and age of onset. IRDs are caused by mutations in >250 genes. Variants in the RPE65 gene account for 0.6-6% of RP and 3-16% of LCA/EORD cases. Voretigene neparvovec is a gene therapy approved for the treatment of patients with an autosomal recessive retinal dystrophy due to confirmed biallelic RPE65 variants (RPE65-IRDs). Therefore, the accurate molecular diagnosis of RPE65-IRDs is crucial to identify 'actionable' genotypes-i.e., genotypes that may benefit from the treatment-and is an integral part of patient management. To date, hundreds of RPE65 variants have been identified, some of which are classified as pathogenic or likely pathogenic, while the significance of others is yet to be established. In this review, we provide an overview of the genetic diagnostic workup needed to select patients that could be eligible for voretigene neparvovec treatment. Careful clinical characterization of patients by multidisciplinary teams of experts, combined with the availability of next-generation sequencing approaches, can accelerate patients' access to available therapeutic options.


Assuntos
Oftalmopatias Hereditárias/genética , Doenças Retinianas/genética , cis-trans-Isomerases/genética , Oftalmopatias Hereditárias/diagnóstico , Oftalmopatias Hereditárias/terapia , Aconselhamento Genético , Testes Genéticos/métodos , Terapia Genética , Variação Genética , Genótipo , Humanos , Mutação , Doenças Retinianas/diagnóstico , Doenças Retinianas/terapia
8.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202474

RESUMO

Salivary gland tumors are a rare tumor entity within malignant tumors of all tissues. The most common are malignant mucoepidermoid carcinoma, adenoid cystic carcinoma, and acinic cell carcinoma. Pleomorphic adenoma is the most recurrent form of benign salivary gland tumor. Due to their low incidence rates and complex histological patterns, they are difficult to diagnose accurately. Malignant tumors of the salivary glands are challenging in terms of differentiation because of their variability in histochemistry and translocations. Therefore, the primary goal of the study was to review the current literature to identify the recent developments in histochemical diagnostics and translocations for differentiating salivary gland tumors.


Assuntos
Biomarcadores Tumorais , Predisposição Genética para Doença , Testes Genéticos , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/genética , Translocação Genética , Estudos de Associação Genética , Testes Genéticos/métodos , Testes Genéticos/normas , Humanos , Gradação de Tumores , Estadiamento de Neoplasias , Cuidados Pré-Operatórios/métodos , Cuidados Pré-Operatórios/normas , Neoplasias das Glândulas Salivares/metabolismo , Neoplasias das Glândulas Salivares/terapia
10.
Nat Commun ; 12(1): 4418, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285202

RESUMO

Studies of the genetic basis of complex traits have demonstrated a substantial role for common, small-effect variant polygenic burden (PB) as well as large-effect variants (LEV, primarily rare). We identify sufficient conditions in which GWAS-derived PB may be used for well-powered rare pathogenic variant discovery or as a sample prioritization tool for whole-genome or exome sequencing. Through extensive simulations of genetic architectures and generative models of disease liability with parameters informed by empirical data, we quantify the power to detect, among cases, a lower PB in LEV carriers than in non-carriers. Furthermore, we uncover clinically useful conditions wherein the risk derived from the PB is comparable to the LEV-derived risk. The resulting summary-statistics-based methodology (with publicly available software, PB-LEV-SCAN) makes predictions on PB-based LEV screening for 36 complex traits, which we confirm in several disease datasets with available LEV information in the UK Biobank, with important implications on clinical decision-making.


Assuntos
Predisposição Genética para Doença , Testes Genéticos/métodos , Modelos Genéticos , Herança Multifatorial/genética , Tomada de Decisão Clínica/métodos , Conjuntos de Dados como Assunto , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Software , Sequenciamento Completo do Genoma
11.
J Alzheimers Dis ; 82(2): 761-770, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34092641

RESUMO

BACKGROUND: Rare variants of SORL1 have been associated with an increased risk of early-onset or late-onset Alzheimer's disease (AD). However, a lot remains to be clarified about their significance in the pathogenesis of the disease. OBJECTIVE: To evaluate the role of SORL1 variants among Finnish patients with early-onset AD (EOAD). METHODS: The rare SORL1variants were screened in a cohort of 115 Finnish EOAD patients (mean age at onset 58.3 years, range 46-65 years) by using the whole-exome sequencing. RESULTS: We found one novel nonsense variant (p.Gln290*) and eight missense variants in SORL1. This is the first study reporting the SORL1 variants p.Lys80Arg, p.Ala789Val and p.Arg866Gln in EOAD patients. Furthermore, two of these three missense variants were overrepresented in EOAD patients compared to gnomAD non-neuro Finnish samples. CONCLUSION: This study strengthens the earlier findings, that the rare variants in SORL1 are associated with EOAD.


Assuntos
Doença de Alzheimer , Testes Genéticos , Proteínas Relacionadas a Receptor de LDL/genética , Proteínas de Membrana Transportadoras/genética , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/genética , Doença de Alzheimer/psicologia , Precursor de Proteína beta-Amiloide/metabolismo , Transporte Biológico Ativo/fisiologia , Estudos de Coortes , Feminino , Finlândia/epidemiologia , Predisposição Genética para Doença , Testes Genéticos/métodos , Testes Genéticos/estatística & dados numéricos , Variação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Polimorfismo de Nucleotídeo Único
12.
Commun Biol ; 4(1): 736, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127790

RESUMO

Aggregates of hyperphosphorylated tau protein are a pathological hallmark of more than 20 distinct neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, and frontotemporal dementia. While the exact mechanism of tau aggregation is unknown, the accumulation of aggregates correlates with disease progression. Here we report a genome-wide CRISPR screen to identify modulators of endogenous tau protein for the first time. Primary screens performed in SH-SY5Y cells, identified positive and negative regulators of tau protein levels. Hit validation of the top 43 candidate genes was performed using Ngn2-induced human cortical excitatory neurons. Using this approach, genes and pathways involved in modulation of endogenous tau levels were identified, including chromatin modifying enzymes, neddylation and ubiquitin pathway members, and components of the mTOR pathway. TSC1, a critical component of the mTOR pathway, was further validated in vivo, demonstrating the relevance of this screening strategy. These findings may have implications for treating neurodegenerative diseases in the future.


Assuntos
Redes e Vias Metabólicas/genética , Neurônios/metabolismo , Proteínas tau/metabolismo , Animais , Proteína 9 Associada à CRISPR , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Edição de Genes , Genes/genética , Genes/fisiologia , Testes Genéticos/métodos , Estudo de Associação Genômica Ampla , Humanos , Camundongos , Neuroblastoma/metabolismo , Ratos , Serina-Treonina Quinases TOR/metabolismo
13.
Genes (Basel) ; 12(5)2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065235

RESUMO

Pathological mutations in homology-directed repair (HDR) genes impact both future cancer risk and therapeutic options for patients. HDR is a high-fidelity DNA repair pathway for resolving DNA double-strand breaks throughout the genome. BRCA2 is an essential protein that mediates the loading of RAD51 onto resected DNA breaks, a key step in HDR. Germline mutations in BRCA2 are associated with an increased risk for breast, ovarian, prostate, and pancreatic cancer. Clinical findings of germline or somatic BRCA2 mutations in tumors suggest treatment with platinum agents or PARP inhibitors. However, when genetic analysis reveals a variant of uncertain significance (VUS) in the BRCA2 gene, precision medicine-based decisions become complex. VUS are genetic changes with unknown pathological impact. Current statistics indicate that between 10-20% of BRCA sequencing results are VUS, and of these, more than 50% are missense mutations. Functional assays to determine the pathological outcome of VUS are urgently needed to provide clinical guidance regarding cancer risk and treatment options. In this review, we provide a brief overview of BRCA2 functions in HDR, describe how BRCA2 VUS are currently assessed in the clinic, and how genetic and biochemical functional assays could be integrated into the clinical decision process. We suggest a multi-step workflow composed of robust and accurate functional assays to correctly evaluate the potential pathogenic or benign nature of BRCA2 VUS. Success in this precision medicine endeavor will offer actionable information to patients and their physicians.


Assuntos
Proteína BRCA2/genética , Tomada de Decisão Clínica/métodos , Testes Genéticos/métodos , Síndrome Hereditária de Câncer de Mama e Ovário/genética , Proteína BRCA2/metabolismo , Feminino , Teste de Complementação Genética/métodos , Síndrome Hereditária de Câncer de Mama e Ovário/diagnóstico , Síndrome Hereditária de Câncer de Mama e Ovário/terapia , Humanos , Mutação , Fluxo de Trabalho
14.
Genes (Basel) ; 12(5)2021 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-34065301

RESUMO

BACKGROUND: We investigated the mutational landscape of skin tumors in patients with Muir-Torre Syndrome (MTS) a hereditary autosomal dominant mismatch repair disorder of increased cancer susceptibility, and examined mutations other than in the DNA mismatch repair (MMR) genes. METHODS: This retrospective single-center case series included seven patients with the diagnosis of Muir-Torre Syndrome with precise medical history and family history. Mutational analysis of tumor samples Formalin-fixed paraffin-embedded tissue blocks of skin lesions associated with Muir-Torre Syndrome were used for further analysis. All skin tumors were analyzed with the Oncomine Comprehensive Assay v3 (Life Technologies), which includes 161 of the most relevant cancer driver genes. RESULTS: Eleven skin neoplasms (nine sebaceous tumors, one melanoma, one cutaneous squamous cell carcinoma) were diagnosed in seven patients. In two patients, visceral malignancies preceded the diagnosis of the skin tumors and one patient was diagnosed with a visceral malignancy after a sebaceous tumor. History of familial cancer of Lynch Syndrome (LS) was reported in three patients. The most frequently detected mutation was in the MSH2 gene, followed by mutations in the NOTCH1/2 and TP53 gene. Conclusion, this study provides a molecular analysis of Muir-Torre Syndrome associated and non-associated skin tumors in patients with Muir-Torre Syndrome. Patients with sebaceous lesions should undergo microsatellite instability analysis and accurate evaluation of personal and family history to detect a possible Muir-Torre syndrome. As secondary malignancies may appear years after the first occurrence of sebaceous tumors, lifelong screening is mandatory.


Assuntos
Carcinoma de Células Escamosas/genética , Testes Genéticos/métodos , Melanoma/genética , Síndrome de Muir-Torre/genética , Neoplasias Cutâneas/genética , Idoso , Carcinoma de Células Escamosas/patologia , Feminino , Testes Genéticos/normas , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/normas , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Síndrome de Muir-Torre/patologia , Proteína 2 Homóloga a MutS/genética , Mutação , Receptor Notch1/genética , Receptor Notch2/genética , Análise de Sequência de DNA/métodos , Análise de Sequência de DNA/normas , Neoplasias Cutâneas/patologia , Proteína Supressora de Tumor p53/genética
15.
Genes (Basel) ; 12(5)2021 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-34065872

RESUMO

Precision medicine is a medical approach to administer patients with a tailored dose of treatment by taking into consideration a person's variability in genes, environment, and lifestyles. The accumulation of omics big sequence data led to the development of various genetic databases on which clinical stratification of high-risk populations may be conducted. In addition, because cancers are generally caused by tumor-specific mutations, large-scale systematic identification of single nucleotide polymorphisms (SNPs) in various tumors has propelled significant progress of tailored treatments of tumors (i.e., precision oncology). Machine learning (ML), a subfield of artificial intelligence in which computers learn through experience, has a great potential to be used in precision oncology chiefly to help physicians make diagnostic decisions based on tumor images. A promising venue of ML in precision oncology is the integration of all available data from images to multi-omics big data for the holistic care of patients and high-risk healthy subjects. In this review, we provide a focused overview of precision oncology and ML with attention to breast cancer and glioma as well as the Bayesian networks that have the flexibility and the ability to work with incomplete information. We also introduce some state-of-the-art attempts to use and incorporate ML and genetic information in precision oncology.


Assuntos
Neoplasias da Mama/genética , Biologia Computacional/métodos , Testes Genéticos/métodos , Medicina de Precisão/métodos , Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Aprendizado de Máquina , Polimorfismo de Nucleotídeo Único
16.
Genes (Basel) ; 12(5)2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-34066437

RESUMO

The identification of neurological disorders by next-generation sequencing (NGS)-based gene panels has helped clinicians understand the underlying physiopathology, resulting in personalized treatment for some rare diseases. While the phenotype of distinct neurogenetic disorders is generally well-known in childhood, in adulthood, the phenotype can be unspecific and make the standard diagnostic approach more complex. Here we present three unrelated adults with various neurological manifestations who were successfully diagnosed using NGS, allowing for the initiation of potentially life-changing treatments. A 63-year-old woman with progressive cognitive decline, pyramidal signs, and bilateral cataract was treated by chenodeoxycholic acid following the diagnosis of cerebrotendinous xanthomatosis due to a homozygous variant in CYP27A1. A 32-year-old man with adult-onset spastic paraplegia, in whom a variant in ABCD1 confirmed an X-linked adrenoleukodystrophy, was treated with corticoids for adrenal insufficiency. The third patient, a 28-year-old woman with early-onset developmental delay, epilepsy, and movement disorders was treated with a ketogenic diet following the identification of a variant in SLC2A1, confirming a glucose transporter type 1 deficiency syndrome. This case study illustrates the challenges in the timely diagnosis of medically actionable neurogenetic conditions, but also the considerable potential for improving patient health through modern sequencing technologies.


Assuntos
Adrenoleucodistrofia/genética , Erros Inatos do Metabolismo dos Carboidratos/genética , Testes Genéticos/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Proteínas de Transporte de Monossacarídeos/deficiência , Xantomatose Cerebrotendinosa/genética , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genética , Adrenoleucodistrofia/diagnóstico , Adulto , Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Colestanotriol 26-Mono-Oxigenase/genética , Feminino , Transportador de Glucose Tipo 1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Transporte de Monossacarídeos/genética , Análise de Sequência de DNA/métodos , Xantomatose Cerebrotendinosa/diagnóstico
17.
Genes (Basel) ; 12(6)2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34071827

RESUMO

With limited access to trained clinical geneticists and/or genetic counselors in the majority of healthcare systems globally, and the expanding use of genetic testing in all specialties of medicine, many healthcare providers do not receive the relevant support to order the most appropriate genetic test for their patients. Therefore, it is essential to educate all healthcare providers about the basic concepts of genetic testing and how to properly utilize this testing for each patient. Here, we review the various genetic testing strategies and their utilization based on different clinical scenarios, and test characteristics, such as the types of genetic variation identified by each test, turnaround time, and diagnostic yield for different clinical indications. Additional considerations such as test cost, insurance reimbursement, and interpretation of variants of uncertain significance are also discussed. The goal of this review is to aid healthcare providers in utilizing the most appropriate, fastest, and most cost-effective genetic test for their patients, thereby increasing the likelihood of a timely diagnosis and reducing the financial burden on the healthcare system by eliminating unnecessary and redundant testing.


Assuntos
Testes Genéticos/métodos , Pediatria/métodos , Guias de Prática Clínica como Assunto , Sequenciamento Completo do Genoma/métodos , Testes Genéticos/normas , Humanos , Pediatria/normas , Medicina de Precisão/métodos , Medicina de Precisão/normas , Sequenciamento Completo do Genoma/normas
18.
EBioMedicine ; 69: 103446, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34157485

RESUMO

BACKGROUND: Breast cancers can be divided into HER2-negative and HER2-positive subtypes according to different status of HER2 gene. Despite extensive studies connecting germline mutations with possible risk of HER2-negative breast cancer, the main category of breast cancer, it remains challenging to obtain accurate risk assessment and to understand the potential underlying mechanisms. METHODS: We developed a novel framework named Damage Assessment of Genomic Mutations (DAGM), which projects rare coding mutations and gene expressions into Activity Profiles of Signalling Pathways (APSPs). FINDINGS: We characterized and validated DAGM framework at multiple levels. Based on an input of germline rare coding mutations, we obtained the corresponding APSP spectrum to calculate the APSP risk score, which was capable of distinguish HER2-negative from HER2-positive cases. These findings were validated using breast cancer data from TCGA (AUC = 0.7). DAGM revealed that HER2 signalling pathway was up-regulated in germline of HER2-negative patients, and those with high APSP risk scores had exhibited immune suppression. These findings were validated using RNA sequencing, phosphoproteome analysis, and CyTOF. Moreover, using germline mutations, DAGM could evaluate the risk for HER2-negative breast cancer, not only in women carrying BRCA1/2 mutations, but also in those without known disease-associated mutations. INTERPRETATION: The DAGM can facilitate the screening of subjects at high risk of HER2-negative breast cancer for primary prevention. This study also provides new insights into the potential mechanisms of developing HER2-negative breast cancer. The DAGM has the potential to be applied in the prevention, diagnosis, and treatment of HER2-negative breast cancer. FUNDING: This work was supported by the National Key Research and Development Program of China (grant no. 2018YFC0910406 and 2018AAA0103302 to CZ); the National Natural Science Foundation of China (grant no. 81202076 and 82072939 to MY, 81871513 to KW); the Guangzhou Science and Technology Program key projects (grant no. 2014J2200007 to MY, 202002030236 to KW); the National Key R&D Program of China (grant no. 2017YFC1309100 to CL); Shenzhen Science and Technology Planning Project (grant no. JCYJ20170817095211560 574 to YN); and the Natural Science Foundation of Guangdong Province (grant no. 2017A030313882 to KW and S2013010012048 to MY); Hefei National Laboratory for Physical Sciences at the Microscale (grant no. KF2020009 to GN); and RGC General Research Fund (grant no. 17114519 to YQS).


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Receptor ErbB-2/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Transdução de Sinais , Transcriptoma
19.
EBioMedicine ; 69: 103322, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34161886

RESUMO

BACKGROUND: Hereditary hearing loss (HHL) is the most common sensory deficit, which highly afflicts humans. With gene sequencing technology development, more variants will be identified and support genetic diagnoses, which is difficult for human experts to diagnose. This study aims to develop a machine learning-based genetic diagnosis model of HHL-related variants of GJB2, SLC26A4 and MT-RNR1. METHODS: This case-control study included 1898 subjects, among which 1354 were HHL patients and 544 were carriers. Risk assessment models were established based on variants at 144 sites in three genes related to HHL by building six machine learning (ML) models. We compared the ML models with the genetic risk score (GRS) and expert interpretation (EI) to verify the clinical performance. FINDINGS: Among the six ML models, the support vector machine (SVM) showed the best performance. For the prediction of HHL-related gene sites in subjects with variants, the area under the receiver operating characteristic (AUC) of the SVM model was 0.803 (0.680-0.814) in the 10-fold stratified cross-validation and 0.751 (0.635-0.779) in external validation. The predicted results were better than both EI and GRS. Furthermore, 11 sites were identified as the smallest feature set that can be accurately predicted. INTERPRETATION: The developed SVM model has great potential to be an efficient and effective tool for HHL prediction when high throughput sequencing data are available. FUNDING: This study was supported by the National Key Research and Development Program (2017YFC1001800).


Assuntos
Conexina 26/genética , Diagnóstico por Computador/métodos , Testes Genéticos/métodos , Perda Auditiva Neurossensorial/genética , RNA Ribossômico/genética , Transportadores de Sulfato/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Perda Auditiva Neurossensorial/diagnóstico , Humanos , Lactente , Masculino , Mutação , Máquina de Vetores de Suporte
20.
Medicine (Baltimore) ; 100(23): e26323, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34115047

RESUMO

RATIONALE: B-lymphoblastic lymphoma (B-LBL) with BCR/ABL mutation (Ph+ B-LBL) is a rare type of cancer in both childhood and adults. Its clinical manifestations are similar to those of other types lymphoma. However, the targeted therapy can substantially improve the outcome of Ph+ B-LBL. PATIENT CONCERNS: A 19-year-old male with blood type O, Rh+ was admitted into our hospital on August 14, 2018, due to a recurrent fever and hypocytosis for 6 months. DIAGNOSES: Routine blood exam showed pancytopenia. Bone marrow sample flow cytometry (FCM) exam showed abnormal cells were 2.27% of the nucleated cells, and was classified as the abnormal early B-lineage lymphoblastic cells. FISH testing showed the BCR/ABL positive cells were 13.6%. Karyotype analysis showed the 46, XY, t(9;22)(q34;q11). Molecular analysis of BCR/ABL mutation on ABL kinase showed that BCR/ABL T315I mutation. Patient was diagnosed with B-LBL with BCR/ABL mutation (Ph+ B-LBL). INTERVENTIONS: The patient was given chemotherapy with VDPI regimen (Vinorelbine, daunorubicin, prednisone, imatinib). OUTCOMES: The patient achieved complete remission after 2 courses' treatment, followed by one course of clarithromycin regimen and another two courses of VDPI regimen. Patient remains in complete remission as of March 10, 2021. LESSONS: In B-LBL, a BCR/ABL mutation can happen in some of these patients. It is important to guide the pathologist to perform appropriate gene mutation detection, in addition to routine Immunohistochemistry test, to ensure an accurate diagnosis and use the targeted agent for treatment. According to the literature and our results, it seems that intensive chemotherapy plus TKI regimen is effective in inducing complete remission, and allo-SCT should be used as a long-term strategy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Proteínas de Fusão bcr-abl/genética , Mesilato de Imatinib/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras , Exame de Medula Óssea/métodos , Daunorrubicina/administração & dosagem , Testes Genéticos/métodos , Humanos , Masculino , Mutação , Variantes Farmacogenômicos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatologia , Prednisona/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Indução de Remissão/métodos , Resultado do Tratamento , Vincristina/administração & dosagem , Adulto Jovem
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